The Impact of HBV Therapy on Fibrosis and Cirrhosis Jordan J. Feld, MD, MPH Associate Professor of Medicine University of Toronto Hepatologist Toronto Centre for Liver Disease Sandra Rotman Centre for Global Health Toronto, Canada This program is supported by an educational grant from Gilead Sciences
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Disclosures Jordan J. Feld, MD, MPH, has disclosed that he has received funds for research support from Abbott, AbbVie, Gilead Sciences, Janssen, Merck, and Regulus and consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck.
What Happens After HBeAg Loss? HBeAg+ HBeAg- HBeAb+ Immune tolerance Immune clearance HBV DNA Progressive fibrosis ALT Infection Mos-Yrs Progressive fibrosis may occur more rapidly in HBV than in HCV infection Slide courtesy of Jordan J. Feld, MD, MPH.
Risk Factors for Progressive Fibrosis Host: Male sex Increasing age Metabolic syndrome Alcohol consumption Coinfections HCV, HDV, HIV Virus: HBV DNA levels (except for immune tolerant) HBeAg positive HBV genotype (?) C > B > A/D
REVEAL: HBV DNA Level and Risk of Cirrhosis Long-term (mean follow-up: 11.4 yrs) cohort study to determine risk of cirrhosis and HCC in untreated, HBsAg-positive individuals in Taiwan (N = 3582) Cumulative Incidence of Liver Cirrhosis.4.3.2.1 Baseline HBV DNA Level (copies/ml) 1 million 1,-999,999 1,-99,999 3-9999 < 3 1 2 3 4 5 6 7 8 9 1 11 12 13 Iloeje UH, et al. Gastroenterology. 26;13:678-686. Follow-up (Yrs)
REVEAL: HBV DNA Level and Risk of HCC Prospective study in same REVEAL cohort (N = 3653) Cumulative Incidence of HCC (%) 14 12 1 Increased HCC incidence with increasing DNA levels (P <.1) HCC can occur in the absence of cirrhosis Chen CJ, et al. JAMA. 26;295:65-73. 8 6 4 2 Baseline HBV DNA (copies/ml) 1 million 1,-999,999 1,-99,999 3-9999 < 3 1 2 3 4 5 6 7 8 9 1 11 12 13 Follow-up (Yrs)
REVEAL: Risk Factors for HCC Factor Adjusted HR 95% CI P Value Male sex 2.1 1.3-3.3.3 Age (per yr) 1.9 1.7-1.11 <.1 HBeAg positive 2.6 1.6-4.2 <.1 Cirrhosis 9.1 5.9-13.9 <.1 HBV DNA (copies/ml) < 3 3-9999 1,-99,999 1,-999,999 1,, *P value for trend. 1. 1.1 2.3 6.6 6.1 Ref.5-2.3 1.1-4.9 3.3-13.1 2.9-12.7 <.1*.86.2 <.1 <.1 Chen CJ, et al. JAMA. 26;295:65-73.
Does Therapy Change the Outcome?
HBV Treatment Reduces Risk of Disease Progression Including Decompensation Placebo-controlled, double-blind, parallel group study of pts with chronic HBV infection and cirrhosis (F4) (N = 651) followed until HBeAg seroconversion or disease progression* 25 Pts With Disease Progression (%) 2 15 1 5 n = 198 Liaw YF, et al. N Engl J Med. 24;351:1521-1531. n = 417 n = 385 n = 173 Lamivudine P =.1 6 12 18 24 3 36 Mos *Hepatic decompensation, HCC, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease. Placebo n = 43 n = 122
HBV Treatment Reduces Risk of Liver Transplant Prospective cohort study in pts with HBV and first-onset complications of decompensated cirrhosis (N = 77) Treated,* responder (n = 245) 1 Treated,* nonresponder (n = 178) Untreated (n = 284) LT-Free Survival (%) 8 6 4 2 Bonferroni-adjusted P <.3 12 24 36 48 6 72 84 Mos *Treated predominantly with lamivudine (n = 23) or entecavir (n = 198). Antiviral therapy improved transplant-free survival over 5 yrs (P =.98 vs untreated) Jang JW, et al. Hepatology. 215;61:189-182.
Many HBV Treatment Endpoints Indicate None Is Ideal; Need to Use Surrogates Complications take yrs to decades to develop difficult to use as treatment endpoints Instead we use surrogate endpoints: Biochemical Normalization of ALT Serologic HBeAg loss and/or seroconversion for HBeAg positive HBV Ideally HBsAg loss and/or seroconversion Virologic Histologic
Long-term TDF in Pts With HBV: Reversal of Inflammation Open-label study of TDF in pts with chronic HBV infection (N = 585) Parameter Outcome at 7 Yrs Necroinflammation improved over [1] 5 yrs (n = 348 matched biopsies) [2] Normalized ALT, % (n/n) ITT* On treatment HBV DNA < 29 IU/mL, % (n/n) ITT On treatment 57.1 (323/566) 8. (328/41) 7.1 (418/596) 99.3 (43/433) HBeAg loss, % (n/n) 54.5 (84/154) HBe seroconversion, % (n/n) HBsAg loss, K-M % (95% CI) HBs seroconversion, K-M % (95% CI) 39.6 (61/154) 11.8 (8.1, 16.9) 9.7 (6.4, 14.6) *Pts with data missing or FTC added counted as failures. HBeAg-positive population. 1. Buti M, et al. Dig Dis Sci. 215;6:1457-1464. 2. Marcellin P, et al. Lancet. 213;381:468-475. Pts (%) 1 8 6 4 2 Knodell Necroinflammatory Score 1-14 P <.1 8% 7-9 4-6 -3 P <.1 Baseline Yr 1 Yr 5 8%
Long-term TDF in Pts With HBV: Regression of Fibrosis, Cirrhosis Overall regression of fibrosis in 51% of pts through 5 yrs (176/348 pts with matched biopsies) Reversal of cirrhosis in 74% of pts through 5 yrs (71/96 pts with cirrhosis at baseline) Pts (%) 1 8 6 4 2 P <.1 38% 39% P <.1 12% 63% Ishak Fibrosis Score 6 5 4 3 2 1 Baseline Yr 1 Yr 5 Marcellin P, et al. Lancet. 213;381:468-475.
Long-term Entecavir in Pts With HBV: Reversal of Inflammation Histologic and virologic improvements evaluated by liver biopsy in HBV pts (N = 69) with 3-yr cumulative entecavir treatment Median time on entecavir: 6 yrs (range: 3-7) Parameter, % (n/n) ALT 1 x upper limit of normal HBV DNA < 3 copies/ml Outcome 86 (49/57) 1 (57/57) HBeAg loss 55 (22/4) HBe seroconversion 33 (13/4) HBsAg loss (/56) Pts (n) 6 5 4 3 2 1 Knodell Necroinflammatory Score 1-14 7-9 4-6 -3 Missing Baseline Wk 48 Long Term Chang TT, et al. Hepatology. 21;52:886-893.
Long-term Entecavir in Pts With HBV: Regression of Fibrosis, Cirrhosis Regression of fibrosis ( 1-point decrease in Ishak score) in 88% of pts (5/57 pts with matched biopsies and baseline Knodell scores 2) Reversal of cirrhosis in 4/1 pts with cirrhosis at baseline (median decrease in Ishak score: 3 points) Pts (n) 6 5 4 3 2 1 n = 57 matched biopsies Baseline Wk 48 Long Term Chang TT, et al. Hepatology. 21;52:886-893. Ishak Fibrosis Score 6 5 4 3 2 1 Missing
HCC Incidence in Pts With Chronic HBV Infection 5-Yr Cumulative Incidence of HCC 4 3 2 1 n = ahr:.55 (95% CI:.31-.99) 13.8 26.4 482 69 Hong Kong [1] (Cirrhosis only) ahr:.31 (95% CI:.27-.53) 6.62 21,595 19.8 21,595 7. 38.9 79 85 Taiwan* [2] Japan [3] (Cirrhosis only) *Incidence rates include cirrhotic pts (13.6% of pts had cirrhosis at baseline) and noncirrhotic pts. Nucleos(t)ide analogues Control 1. Wong GL, et al. Hepatology. 213;5:1537-1547. 2. Wu CY, et al. Gastroenterology. 214;147:143-151. 3. Hosaka T, et al. Hepatology. 213;58:98-17.
HCC Incidence in Pts With Chronic HBV Infection but Without Cirrhosis 5-Yr Cumulative Incidence of HCC 4 3 2 1 n = 3.3 3. 984 355 Hong Kong [1] (No cirrhosis) Greater benefit in pts with cirrhosis ahr:.31 (95% CI:.27-.53) 6.62 21,595 19.8 21,595 2.5 3.6 237 231 Taiwan* [2] Japan [3] (No cirrhosis) *Incidence rates include cirrhotic pts (13.6% of pts had cirrhosis at baseline) and noncirrhotic pts. Nucleos(t)ide analogues Control 1. Wong GL, et al. Hepatology. 213;5:1537-1547. 2. Wu CY, et al. Gastroenterology. 214;147:143-151. 3. Hosaka T, et al. Hepatology. 213;58:98-17.
Is HBV Suppression the Same as Inactive Disease? Retrospective cohort study of treatment-naive pts with HBV starting oral nucleos(t)ide analogues (n = 1378) vs HBeAg-negative pts with inactive CHB (n = 114) Group receiving nucleos(t)ide analogues divided by continuous viral suppression (complete vs incomplete responder) Spontaneous control better than treatment Cumulative Incidence of HCC (%) Pts at Risk, n NUC CR Inactive CHB 6 5 4 3 2 1 P <.1 Complete responders Mos Inactive CHB 12 24 36 48 6 72 1132 114 848 918 564 724 497 594 38 469 128 34 19 8 Cho JY, et al. Gut. 214;63:1943-195.
Reduction in HCC Mortality Through National Viral Hepatitis Therapy Program Pts receiving treatment for chronic hepatitis after start of program in 23 in Taiwan: 157,57 (HBV) and 61,823 (HCV) Reduced rate of HCC mortality in all age cohorts by 5-8 yrs after introduction of national therapy program 2-23 1. 1. 1. 1. 1..98 24-27.93*.92*.88* 28-211.79.8.76.77.66 Sex-Adjusted HCC Mortality Rate Ratio.6.4.2 3-39 4-49 5-59 *P <.1 vs 2-23. Age Group (Yrs) P <.5 vs 2-23. 6-69 Chiang CJ, et al. Hepatology. 215;61:1154-1162.
Identifying Risk of HCC: Transient Elastography vs Biomarkers Retrospective study comparing prognostic performance of TE vs FIB-4 serological biomarker score to identify risk of HCC in pts with CHB (N = 138) Cumulative Incidence.4.3.2.1 TE LSM 8 kpa 8 < LSM 13 kpa 13 < LSM 18 kpa 18 < LSM 23 kpa LSM > 23 kpa FIB-4 1 2 3 4 5 6 7 1 2 3 4 5 6 Yrs Yrs TE was more accurate than FIB-4 at identifying low HCC risk Cumulative Incidence.4.3.2.1 FIB-4 < 1.25 1.25 FIB-4 < 1.7 1.7 FIB-4 < 2.4 FIB-4 2.4 7 Kim SU, et al. Medicine (Baltimore). 216;95:e3434.
Based on This... Whom and How Should We Treat?
Updated AASLD Guidelines: When to Treat HBV DNA, IU/mL HBeAg Positive ALT Histologic Disease HBV DNA, IU/mL HBeAg Negative ALT Histologic Disease Any > 2 x ULN N/A Any > 2 x ULN N/A > 2, Any Any > 2 Any Any Any Any Cirrhosis Any Any Cirrhosis Changes to guidance: Lower threshold for treating HBeAg-negative pts Treat all pts with cirrhosis regardless of HBV DNA Do not stop treatment in HBeAgnegative pts with cirrhosis Terrault NA, et al. Hepatology. 216;63:261-283.
AASLD Guidelines: Initial Treatment Treatment Preferred Notes Entecavir Yes (unless previous history of lamivudine resistance) High potency, high genetic barrier to resistance Tenofovir Yes High potency, high genetic barrier to resistance PegIFN Yes Less safe in pts with cirrhosis Adefovir No Low genetic barrier to resistance Lamivudine No Low genetic barrier to resistance Telbivudine No Low genetic barrier to resistance Treatment with antivirals does not eliminate the risk of HCC, and surveillance for HCC should continue in persons who are at risk Terrault NA, et al. Hepatology. 216;63:261-283.
TAF vs TDF in Pts With HBV Infection: Efficacy Multicenter phase III studies in pts with chronic HBV infection (N = 1298), including pts with compensated cirrhosis HBeAg-Positive Pts [2] (N = 873) HBeAg-Negative Pts [3] (N = 425) Outcome, % TAF TDF P Value TAF TDF P Value HBV DNA < 29 IU/mL at Wk 72 [1] 71.6 71.9.78 92.6 92.1.84 ALT normalization at Wk 48 Central laboratory criteria* AASLD laboratory criteria 72 45 67 36.18.14 83 5 75 32.76 <.1 HBeAg Loss at Wk 48 Seroconversion at Wk 48 14 1 12 8.47.32 HBsAg Loss at Wk 48 Seroconversion at Wk 48 <1 <1 <1 *ULN for men, 43 U/L ( 35 U/L if age 69 yrs); for women, 34 U/L ( 32 U/L if age 69 yrs). ULN for men, 3 U/L; for women, 19 U/L. 1. Seto WK, et al. AASLD 216. Abstract 67. 2. Chan HL, et al. EASL 216. Abstract GS12. 3. Buti M, et al. EASL 216. Abstract GS6..52.22
TAF vs TDF in Pts With HBV Infection: Safety Multicenter phase III studies in pts with chronic HBV infection (N = 1298), including pts with compensated cirrhosis Outcome TAF TDF P Value Mean change in BMD at Wk 72, % [1] Hip Spine -.16 -.57-1.86-2.37 <.1 <.1 Median change in serum creatinine at Wk 48, mg/dl [2].1.2.12 Median change in egfr at Wk 48, ml/min [2] -1.2-5.4 <.1 Mean change in FibroTest score at Wk 48 [3] HBeAg-positive pts HBeAg-negative pts -.7 -.5 -.4 -.3.7.28 1. Seto WK, et al. AASLD 216. Abstract 67. 2. Agarwal K, et al. AASLD 216. Abstract 1844. 3. Izumi N, et al. AASLD 216. Abstract 194.
Summary HBV is a very dynamic disease Fibrosis may progress quickly both in HBeAg-positive and HBeAg-negative disease Antiviral therapy can: Suppress HBV DNA Reduce inflammation ALT and HAI Reverse fibrosis Reduce the risk of HCC and liver-related events New agents have similar efficacy on surrogate endpoints and a better safety profile
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